: The proposed project is a continuation of the Seveso Women's Health Study (SWHS), ongoing since 1996 (R01ES07171). The original purpose of the SWHS was to investigate the relationship of 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD, or dioxin) and endometriosis in a nested case-control study embedded in a cohort of women exposed to extremely high levels of dioxin as a result of a chemical plant explosion in 1976 in Seveso, Italy. In order to identify cases and controls, the cohort of women aged 0 to 40 years at the time of accident, and who lived in Zone A (n=234) or Zone B (n=1,039) were interviewed extensively about their reproductive and pregnancy histories. Assessments included a blood draw, a pelvic examination, and transvaginal ultrasound. Participants were also asked to complete a menstrual diary. A unique strength of the study is that individual body burden TCDD levels can be measured in sera collected soon after the accident. More than 95% of the women were located twenty years after the accident and roughly 80% of the members of the cohort have participated. The current plan is to analyze the data collected in the SWHS to examine reproductive endpoints other than endometriosis, and to analyze the sera for TCDD necessary to examine these endpoints. In particular, the project will investigate the relationship of TCDD levels in sera with menstrual cycle characteristics (e.g. cycle length and flow), age of menarche, fetal loss, birthweight, clinical infertility, time to conception, and age at menopause. These endpoints were chosen, based on extensive rodent and rhesus monkey data, indicating that exposed animals experience higher rates of fetal mortality and resorption, smaller litter size, lower birthweight, lowered fecundity rates and, more recently, menstrual irregularities, reduced ovulation, delayed onset of puberty, and early onset of menopause. It is because of these animal data that the U.S. Environmental Protection Agency (EPA) is reassessing the allowable exposure levels of TCDD, which is ubiquitous in industrialized areas. There are also concerns that the non-cancer effects of this chemical may be the even more urgent threat to humans. The proposed investigation will be the first comprehensive reproductive health study conducted in human populations exposed to TCDD. If the findings in this highly exposed cohort with well-characterized individual exposure data do not confirm the animal findings, there can be less concern about human health effects, thereby having important policy implications for the regulation of TCDD.